Mechanisms of genetic control of immune responses. I. Evidence for distinct multi-step helper T-cell pathways in cellular and humoral responses to GAT.

We examined multiple genetically regulated humoral and cell-mediated immune (CMI) responses to poly( glu60ala30tyr10 ) (GAT) using a panel of mouse strains. We show that assignment of responder/nonresponder status depends upon the assay method. In addition, two distinct categories of nonresponder mice were found: (1) those which are unresponsive by all parameters tested (H-2q and H-2s haplotypes) and (2) those which are partially nonresponsive [H-2bm12 mutant strain--a low/nonresponder by splenic plaque-forming cell (PFC) and delayed-type hypersensitivity (DTH) responses, but exhibits B6 parental levels of high GAT-specific T-cell proliferation ( Tprlf ) and interleukin-2 production]. The distinction between these two nonresponder types was confirmed by complementation tests in which significant GAT-specific PFC and DTH responses were seen in (H-2q X H-2bm12)F1 hybrids, but not in (H-2q X H-2s)F1 hybrids. Suppressor T cells (Ts) also play a selective role in nonresponsiveness to GAT. Cyclophosphamide treatment of nonresponders (to eliminate Ts activity) as well as immunization with GAT coupled to the immunogenic carrier MBSA result in the development of GAT-specific humoral, but not CMI responses. Our results indicate that the T cell is the cellular site of Ir gene expression and that Tprlf responses do not correlate with functional helper T-cell activity and suggest distinct, multi-step Th/Ts regulatory pathways in the development of humoral and CMI effector functions.